What are alternative TTR stabilizers to tafamidis?

Alternative TTR Stabilizer Medications to Tafamidis

For patients requiring TTR stabilization, diflunisal is the primary alternative to tafamidis, while patisiran, inotersen, and vutrisiran are effective TTR silencer options that can also be considered based on clinical presentation. 1, 2

TTR Stabilizers

Diflunisal

• Mechanism: Non-steroidal anti-inflammatory drug (NSAID) that stabilizes the TTR tetramer
• Evidence: Demonstrated effectiveness in slowing disease progression in ATTRv polyneuropathy 1, 2
• Regulatory status: Not FDA-approved for this indication, used off-label
• Advantages: Lower cost compared to tafamidis 3
• Considerations:
  • Similar efficacy to tafamidis in delaying progression of polyneuropathy and cardiomyopathy 4
  • Binding pattern to TTR closely resembles that observed with tafamidis 4

TTR Silencers (Alternative Approach)

These medications work differently than stabilizers by reducing TTR production rather than stabilizing the protein:

Patisiran

• Dosing: 0.3 mg/kg IV every 3 weeks (maximum 30 mg)
• Mechanism: Small interfering RNA (siRNA)
• FDA approval: Approved for ATTRv polyneuropathy
• Administration considerations:
  • Requires premedication with dexamethasone 10 mg IV, acetaminophen 500 mg, diphenhydramine 50 mg, and famotidine 20 mg at least 60 minutes before infusion
  • Requires vitamin A supplementation (3,000 IU daily) 1, 2

Inotersen

• Dosing: 284 mg SC once weekly
• Mechanism: Antisense oligonucleotide
• FDA approval: Approved for ATTRv polyneuropathy
• Monitoring requirements:
  • Weekly platelet count monitoring
  • Biweekly monitoring of serum creatinine, eGFR, and urine protein-creatinine ratio
  • Requires vitamin A supplementation (3,000 IU daily) 1
• Safety concerns: Risk of thrombocytopenia and glomerulonephritis 1

Vutrisiran

• Dosing: 25 mg SC every 3 months
• Mechanism: Small interfering RNA (siRNA)
• FDA approval: Approved for ATTRv polyneuropathy
• Administration considerations: Requires vitamin A supplementation (3,000 IU daily) 1, 2

Newest FDA-Approved Option

Acoramidis (Attruby)

• Mechanism: Near-complete TTR stabilizer (~96%)
• Evidence: Reduced all-cause mortality by up to 42% and cardiovascular hospitalizations by ~50% in ATTR-CM patients over 30-42 months 2
• FDA approval: Recently approved for ATTR cardiomyopathy 2

Clinical Decision-Making Algorithm

1. Assess disease manifestation:

   • Predominant polyneuropathy: Consider TTR silencers (patisiran, inotersen, or vutrisiran)
   • Predominant cardiomyopathy: Consider acoramidis or diflunisal
   • Mixed presentation: Individualize based on dominant symptoms

2. Consider patient factors:

   • Renal function: Use caution with inotersen in renal impairment
   • Platelet count: Baseline thrombocytopenia may contraindicate inotersen
   • Infusion capability: IV administration required for patisiran
   • Cost considerations: Diflunisal is significantly less expensive

3. Monitoring requirements:

   • All patients on TTR silencers require vitamin A supplementation (3,000 IU daily)
   • Inotersen requires intensive monitoring for thrombocytopenia and nephrotoxicity

Important Caveats

• Early diagnosis and treatment are crucial as patients treated earlier have better outcomes in terms of neuropathy impairment and quality of life 1
• Currently, there is no evidence that TTR stabilizers or silencers benefit polyneuropathy associated with wild-type ATTR amyloidosis 1, 2
• Symptomatic management remains important alongside disease-modifying therapy, including medications for neuropathic pain and treatment of autonomic disorders 1